CINV occurs when the vomiting center located in the lateral reticular formation of the medulla oblongata receives a stimulus. The area postrema and the solitary nucleus of the medulla oblongata contain NK1 receptors, and the NK1 receptors are believed to be closely involved in vomiting.
Administration of an antineoplastic agent facilitates the serotonin secretion from the enterochromaffnm (EC) cells in the digestive tract, and serotonin directly stimulates the vomiting center through 5-hydroxytryptamine3 (5-HT3) receptors in the digestive tract. Also, when serotonin stimulates the vomiting center through the chemoreceptor trigger zone (CTZ) located in the area postrema of the fourth ventricle, nausea and vomiting occur. Substance P, like serotonin, is found in the EC cells in the digestive tract, and its secretion is promoted by administration of an antineoplastic agent. Recently, it has been revealed that substance P induces vomiting through the NK1 receptors in the CTZ or by binding to the NK1 receptors in the central nervous system, and therefore NK1 receptors have been attracting attention as the target for developing antiemetic agents (Non-patent literature 1).
Aprepitant is the first selective NK1 receptor antagonist in the world which was approved as a preventive agent for nausea and vomiting associated with administration of antineoplastic agents. Regarding the mechanism of action of aprepitant, it is believed that aprepitant selectively inhibits the binding of substance P and the NK1 receptors in the central nervous system, which is one of the pathways that induce CINV, and thus prevents CINV. Aprepitant has been launched as a preventive agent for CINV (Non-patent literature 2).
It is known that aprepitant is metabolized by cytochrome P450 (CYP) 3A4. Also, aprepitant is known to have a dose-dependent inhibitory effect on CYP3A4, a CYP3A4-inducing effect and a CYP2C9-inducing effect. Accordingly, aprepitant may cause the drug-drug interactions with drugs that inhibit or induce CYP3A4 or with drugs that are metabolized by CYP3A4 or CYP2C9. For example, it is reported that the inhibitory effect of aprepitant on CYP3A4 sometimes inhibits the metabolism of dexamethasone and that the dose should be thus adjusted when dexamethasone is combined with aprepitant (Non-patent literature 3).
Therefore, when aprepitant is used, sufficient care should be directed to the drug-drug interactions based on the inhibitory effect of aprepitant on CYP3A4.
For the above reasons, a novel NK1 receptor antagonist with fewer drug-drug interactions is required in the prevention or treatment of CINV.
Compounds with an NK1 receptor antagonist activity such as casopitant, netupitant, ezlopitant, rolapitant, vestipitant, vofopitant and so on, are known.
However, casopitant is reported to have an inhibitory effect on CYP3A4 and cause the drug-drug interactions due to the effect (Non-patent literature 4). Clinical trials on casopitant, as a preventive agent for cancer-chemotherapy-induced nausea and vomiting, had been conducted in the U.S. and Europe; however, its development was discontinued after the application. Netupitant is currently under development as a preventive agent for cancer-chemotherapy-induced nausea and vomiting; however, netupitant is reported to have an inhibitory effect on CYP3A4 and cause the drug-drug interactions due to the effect (Non-patent literature 5). Clinical trials on ezlopitant, as a preventive agent for cancer-chemotherapy-induced nausea and vomiting, had been conducted in the U.S.; however, its development was discontinued. Clinical trials on vofopitant, as a preventive agent for cancer-chemotherapy-induced nausea and vomiting, had been conducted in Europe; however, its development was discontinued.
Many of the above compounds resulted in the discontinuance. All the above compounds have not yet on the market.
Pyridine derivatives claiming to be having NK1 receptor antagonist activity are described in Patent literature 1 to 16. And, prodrugs of pyridine derivatives are described in Patent literature 17 and 18.
However, cyclohexyl pyridine derivatives of the present invention are not described in the above literatures.